bims-unfpre 2023-03-12 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2023–03–12
seven papers selected by
Susan Logue, University of Manitoba

Roles of endoplasmic reticulum stress in the pathophysiology of polycystic ovary syndrome.
Potential roles of the endoplasmic reticulum stress pathway in amyotrophic lateral sclerosis.
Emerging roles of endoplasmic reticulum stress in the cellular plasticity of cancer cells.
Anterior gradient 2 induces resistance to sorafenib via endoplasmic reticulum stress regulation in hepatocellular carcinoma.
Stressing out over mucus secretion.
Sustained overexpression of spliced X-box-binding protein-1 in neurons leads to spontaneous seizures and sudden death in mice.
Autophagy is induced by swine acute diarrhea syndrome coronavirus through the cellular IRE1-JNK-Beclin 1 signaling pathway after an interaction of viral membrane-associated papain-like protease and GRP78.

Front Endocrinol (Lausanne). 2023 ;14 1124405

Roles of endoplasmic reticulum stress in the pathophysiology of polycystic ovary syndrome.

Hiroshi Koike, Miyuki Harada, Akari Kusamoto, Zixin Xu, Tsurugi Tanaka, Nanoka Sakaguchi, Chisato Kunitomi, Jerilee M K Azhary, Nozomi Takahashi, Yoko Urata, Yutaka Osuga.

  Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among reproductive-age women, affecting up to 15% of women in this group, and the most common cause of anovulatory infertility. Although its etiology remains unclear, recent research has revealed the critical role of endoplasmic reticulum (ER) stress in the pathophysiology of PCOS. ER stress is defined as a condition in which unfolded or misfolded proteins accumulate in the ER because of an imbalance in the demand for protein folding and the protein-folding capacity of the ER. ER stress results in the activation of several signal transduction cascades, collectively termed the unfolded protein response (UPR), which regulates various cellular activities. In principle, the UPR restores homeostasis and keeps the cell alive. However, if the ER stress cannot be resolved, it induces programmed cell death. ER stress has recently been recognized to play diverse roles in both physiological and pathological conditions of the ovary. In this review, we summarize current knowledge of the roles of ER stress in the pathogenesis of PCOS. ER stress pathways are activated in the ovaries of both a mouse model of PCOS and in humans, and local hyperandrogenism in the follicular microenvironment associated with PCOS is responsible for activating these. The activation of ER stress contributes to the pathophysiology of PCOS through multiple effects in granulosa cells. Finally, we discuss the potential for ER stress to serve as a novel therapeutic target for PCOS.

Keywords:  endoplasmic reticulum stress (ER stress); follicular microenvironment; ovary; pathophysiology; polycystic ovary syndrome (PCOS); unfolded protein response (UPR)

DOI:  https://doi.org/10.3389/fendo.2023.1124405
Front Aging Neurosci. 2023 ;15 1047897

Potential roles of the endoplasmic reticulum stress pathway in amyotrophic lateral sclerosis.

Yu-Mi Jeon, Younghwi Kwon, Shinrye Lee, Hyung-Jun Kim.

  The endoplasmic reticulum (ER) is a major organelle involved in protein quality control and cellular homeostasis. ER stress results from structural and functional dysfunction of the organelle, along with the accumulation of misfolded proteins and changes in calcium homeostasis, it leads to ER stress response pathway such as unfolded protein response (UPR). Neurons are particularly sensitive to the accumulation of misfolded proteins. Thus, the ER stress is involved in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, prion disease and motor neuron disease (MND). Recently, the complex involvement of ER stress pathways has been demonstrated in experimental models of amyotrophic lateral sclerosis (ALS)/MND using pharmacological and genetic manipulation of the unfolded protein response (UPR), an adaptive response to ER stress. Here, we aim to provide recent evidence demonstrating that the ER stress pathway is an essential pathological mechanism of ALS. In addition, we also provide therapeutic strategies that can help treat diseases by targeting the ER stress pathway.

Keywords:  amyotrophic lateral sclerosis; endoplasmic reticulum stress; motor neuron disease; therapeutic target; unfolded protein response

DOI:  https://doi.org/10.3389/fnagi.2023.1047897
Front Oncol. 2023 ;13 1110881

Emerging roles of endoplasmic reticulum stress in the cellular plasticity of cancer cells.

Hao Wang, Kun Mi.

  Cellular plasticity is a well-known dynamic feature of tumor cells that endows tumors with heterogeneity and therapeutic resistance and alters their invasion-metastasis progression, stemness, and drug sensitivity, thereby posing a major challenge to cancer therapy. It is becoming increasingly clear that endoplasmic reticulum (ER) stress is a hallmark of cancer. The dysregulated expression of ER stress sensors and the activation of downstream signaling pathways play a role in the regulation of tumor progression and cellular response to various challenges. Moreover, mounting evidence implicates ER stress in the regulation of cancer cell plasticity, including epithelial-mesenchymal plasticity, drug resistance phenotype, cancer stem cell phenotype, and vasculogenic mimicry phenotype plasticity. ER stress influences several malignant characteristics of tumor cells, including epithelial-to-mesenchymal transition (EMT), stem cell maintenance, angiogenic function, and tumor cell sensitivity to targeted therapy. The emerging links between ER stress and cancer cell plasticity that are implicated in tumor progression and chemoresistance are discussed in this review, which may aid in formulating strategies to target ER stress and cancer cell plasticity in anticancer treatments.

Keywords:  ER stress; cancer stem cell; cellular plasticity; epithelial-mesenchymal plasticity; resistance; vasculogenic mimicry

DOI:  https://doi.org/10.3389/fonc.2023.1110881
Cancer Cell Int. 2023 Mar 10. 23(1): 42

Anterior gradient 2 induces resistance to sorafenib via endoplasmic reticulum stress regulation in hepatocellular carcinoma.

Hung-Wen Tsai, Yi-Li Chen, Chun-I Wang, Ching-Chuan Hsieh, Yang-Hsiang Lin, Pei-Ming Chu, Yuh-Harn Wu, Yi-Ching Huang, Cheng-Yi Chen.

   BACKGROUND: Hepatocellular carcinoma (HCC) accounts for almost 80% of all liver cancer cases and is the sixth most common cancer and the second most common cause of cancer-related death worldwide. The survival rate of sorafenib-treated advanced HCC patients is still unsatisfactory. Unfortunately, no useful biomarkers have been verified to predict sorafenib efficacy in HCC.
RESULTS: We assessed a sorafenib resistance-related microarray dataset and found that anterior gradient 2 (AGR2) is highly associated with overall and recurrence-free survival and with several clinical parameters in HCC. However, the mechanisms underlying the role of AGR2 in sorafenib resistance and HCC progression remain unknown. We found that sorafenib induces AGR2 secretion via posttranslational modification and that AGR2 plays a critical role in sorafenib-regulated cell viability and endoplasmic reticulum (ER) stress and induces apoptosis in sorafenib-sensitive cells. In sorafenib-sensitive cells, sorafenib downregulates intracellular AGR2 and conversely induces AGR2 secretion, which suppresses its regulation of ER stress and cell survival. In contrast, AGR2 is highly intracellularly expressed in sorafenib-resistant cells, which supports ER homeostasis and cell survival. We suggest that AGR2 regulates ER stress to influence HCC progression and sorafenib resistance.
CONCLUSIONS: This is the first study to report that AGR2 can modulate ER homeostasis via the IRE1α-XBP1 cascade to regulate HCC progression and sorafenib resistance. Elucidation of the predictive value of AGR2 and its molecular and cellular mechanisms in sorafenib resistance could provide additional options for HCC treatment.

Keywords:  Anterior gradient 2; Cancer progression; ER stress; Hepatocellular carcinoma; Resistance; Sorafenib

DOI:  https://doi.org/10.1186/s12935-023-02879-w
Cell Host Microbe. 2023 Mar 08. pii: S1931-3128(23)00075-6. [Epub ahead of print]31(3): 327-328

Stressing out over mucus secretion.

Michael J Grey.

In this issue of Cell Host & Microbe, Naama et al. show that autophagy controls mucus secretion in the colons of mice. They demonstrate that autophagy reduces ER stress in mucus-producing goblet cells to enhance mucus production, which shapes the gut microbial community and protects against colitis.

DOI: https://doi.org/10.1016/j.chom.2023.02.005
Commun Biol. 2023 Mar 09. 6(1): 252

Sustained overexpression of spliced X-box-binding protein-1 in neurons leads to spontaneous seizures and sudden death in mice.

Zhuoran Wang, Qiang Li, Brad J Kolls, Brian Mace, Shu Yu, Xuan Li, Wei Liu, Eduardo Chaparro, Yuntian Shen, Lihong Dang, Ángela Del Águila, Joshua D Bernstock, Kory R Johnson, Junjie Yao, William C Wetsel, Scott D Moore, Dennis A Turner, Wei Yang.

The underlying etiologies of seizures are highly heterogeneous and remain incompletely understood. While studying the unfolded protein response (UPR) pathways in the brain, we unexpectedly discovered that transgenic mice (XBP1s-TG) expressing spliced X-box-binding protein-1 (Xbp1s), a key effector of UPR signaling, in forebrain excitatory neurons, rapidly develop neurologic deficits, most notably recurrent spontaneous seizures. This seizure phenotype begins around 8 days after Xbp1s transgene expression is induced in XBP1s-TG mice, and by approximately 14 days post induction, the seizures evolve into status epilepticus with nearly continuous seizure activity followed by sudden death. Animal death is likely due to severe seizures because the anticonvulsant valproic acid could significantly prolong the lives of XBP1s-TG mice. Mechanistically, our gene profiling analysis indicates that compared to control mice, XBP1s-TG mice exhibit 591 differentially regulated genes (mostly upregulated) in the brain, including several GABAA receptor genes that are notably downregulated. Finally, whole-cell patch clamp analysis reveals a significant reduction in both spontaneous and tonic GABAergic inhibitory responses in Xbp1s-expressing neurons. Taken together, our findings unravel a link between XBP1s signaling and seizure occurrence.

DOI: https://doi.org/10.1038/s42003-023-04594-8
PLoS Pathog. 2023 Mar;19(3): e1011201

Autophagy is induced by swine acute diarrhea syndrome coronavirus through the cellular IRE1-JNK-Beclin 1 signaling pathway after an interaction of viral membrane-associated papain-like protease and GRP78.

Da Shi, Ling Zhou, Hongyan Shi, Jiyu Zhang, Jialin Zhang, Liaoyuan Zhang, Dakai Liu, Tingshuai Feng, Miaomiao Zeng, Jianfei Chen, Xin Zhang, Mei Xue, Zhaoyang Jing, Jianbo Liu, Zhaoyang Ji, Haojie He, Longjun Guo, Yang Wu, Jingyun Ma, Li Feng.

Autophagy plays an important role in the infectious processes of diverse pathogens. For instance, cellular autophagy could be harnessed by viruses to facilitate replication. However, it is still uncertain about the interplay of autophagy and swine acute diarrhea syndrome coronavirus (SADS-CoV) in cells. In this study, we reported that SADS-CoV infection could induce a complete autophagy process both in vitro and in vivo, and an inhibition of autophagy significantly decreased SADS-CoV production, thus suggesting that autophagy facilitated the replication of SADS-CoV. We found that ER stress and its downstream IRE1 pathway were indispensable in the processes of SADS-CoV-induced autophagy. We also demonstrated that IRE1-JNK-Beclin 1 signaling pathway, neither PERK-EIF2S1 nor ATF6 pathways, was essential during SADS-CoV-induced autophagy. Importantly, our work provided the first evidence that expression of SADS-CoV PLP2-TM protein induced autophagy through the IRE1-JNK-Beclin 1 signaling pathway. Furthermore, the interaction of viral PLP2-TMF451-L490 domain and substrate-binding domain of GRP78 was identified to activate the IRE1-JNK-Beclin 1 signaling pathway, and thus resulting in autophagy, and in turn, enhancing SADS-CoV replication. Collectively, these results not only showed that autophagy promoted SADS-CoV replication in cultured cells, but also revealed that the molecular mechanism underlying SADS-CoV-induced autophagy in cells.

DOI: https://doi.org/10.1371/journal.ppat.1011201